Secondary Polycythemia

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Background

The word polycythemia indicates increased red blood cells, white blood cells, and platelets. Most of the time, it is used in place of erythrocythemia, or pure red blood cell increase, such as in secondary polycythemia.

The term polycythemia is reserved for the myeloproliferative disorder called polycythemia vera, in which all 3 peripheral blood cell lines can be increased.[1, 2]

Erythrocytosis or erythrocythemia is a more specific term that is used to denote increased red blood cells.[3]

Pathophysiology

Increased hemoglobin and hematocrit values reflect the ratio of red blood cell mass to plasma volume. Any change in either the hemoglobin or the hematocrit can alter test results.

Relative polycythemia, or erythrocythemia, results from decreased plasma volume (G a isb ö ck syndrome). A true polycythemia or erythrocythemia results from increased red blood cell mass. Therefore, hemoglobin and hematocrit levels cannot accurately help make this distinction. Direct measurement of red blood cell mass is necessary to differentiate these conditions.

In primary polycythemia, the disorder results from a mutation expressed within the hematopoietic stem cell or progenitor cells, which drives the eventual accumulation of red blood cells. The secondary polycythemic disorders may be acquired or congenital; however, they are driven by circulating factors that are independent of the function of hematopoietic stem cells.

Epidemiology

Frequency

United States

The frequency of secondary polycythemia depends on the underlying disease.

Mortality/Morbidity

The mortality and morbidity of secondary polycythemia depend on the underlying condition.

History

Patients with a high red blood cell mass usually have plethora or a ruddy complexion. However, if the polycythemia is secondary to hypoxia, as in venous-to-arterial shunts or compromised lung and oxygenation, patients can also appear cyanotic.

Increased red blood cell mass increases blood viscosity and decreases tissue perfusion. With impaired circulation to the central nervous system, patients may present with headaches, lethargy, and confusion or more serious presentations, such as stroke and obtundation. In addition, polycythemia potentially predisposes patients to thrombosis.

Congenital heart diseases manifest at birth or in early childhood. In some cases, a family history of congenital heart disease may be present.

Patients with familial hemoglobinopathies that result in increased oxygen affinity usually have a family history of similar problems in several family members, although significant numbers of patients with congenital polycythemia have no family history of similar disorders.[4]

Chronic pruritus in the absence of a rash is more indicative of a primary myeloproliferative disorder rather than secondary polycythemia.

Physical

Plethora manifests as increased redness of the skin and mucosal membranes. This finding is easier to detect on the palms or soles, where the skin is light in dark-skinned individuals. Some patients may have acrocyanosis caused by sluggish blood flow through small blood vessels.

The presence of splenomegaly supports a diagnosis of polycythemia vera rather than secondary polycythemia. Cardiac murmurs and clubbing of the fingers may suggest a congenital heart disease.

Causes

Secondary polycythemia is defined as an absolute increase in red blood cell mass that is caused by enhanced stimulation of red blood cell production. In contrast, polycythemia vera is characterized by bone marrow with an inherent increased proliferative activity.[1, 3, 5, 6, 7, 8, 9, 10] Approximately two thirds of patients with polycythemia vera have elevated white blood cell (granulocyte, not lymphocyte) counts and platelet counts.[11] No other causes of polycythemia/erythrocytosis are associated with elevated granulocyte or platelet counts.

Enhanced erythroid stimulation can be a physiologic response to generalized or localized tissue hypoxia,[12] as in the following settings:

Impaired perfusion of the kidneys, which may lead to stimulation of erythropoietin [EPO] production, is usually due to local renal hypoxia in the absence of systemic hypoxia. Conditions include the following:

Inappropriate stimulation of EPO production

Inappropriate stimulation of EPO production may occur in the following settings:

Congenital causes

Hemoglobin mutants associated with tight binding to oxygen and a failure to deliver oxygen in the venous blood can cause high EPO levels. The high level of EPO is compensatory to elevate hemoglobin levels to deliver an optimal amount of oxygen to the tissues. Hypoxia-inducible factor 1-alpha (HIF1-alpha) binds to the hypoxia-responsive element, which is downstream of the gene for EPO. The activity of HIF1-alpha is increased by a lowered oxygen tension.

A von Hippel-Lindau gene mutation results in polycythemia by altering the von Hippel-Lindau protein, which plays an important role in sensing hypoxia and binds to hydroxylated HIF1-alpha to serve as a recognition site of an E3-ubiquitin ligase complex. In this condition, and in hypoxia, the undegraded HIF1-alpha forms a heterodimer with HIF-beta and leads to increased transcriptions of the gene for EPO.

Chuvash polycythemia is caused by an autosomal recessive gene mutation on the von Hippel-Lindau gene, which results in the upregulation of the HIF1-alpha target gene and causes elevations in EPO levels.[17]

Low EPO-dependent polycythemias

These are called primary familial and congenital polycythemias.[18] The EPO receptor mutation results in a gain of function, and patients have normal-to-high hematocrit values and low EPO levels.[19] These conditions can be acquired from (1) insulinlike growth factor-1 (IGF-1), a well-known stimulator of erythropoiesis, and (2) cobalt toxicity, which can induce erythropoiesis.

Testosterone-associated polycythemia

The administration of androgen esters to hypogonadal men can lead to polycythemia. However, the incidence of testosterone-associated polycythemia may be lower in men receiving pharmacokinetically steady-state delivery of testosterone formulations, as occurs following the subcutaneous implantation of testosterone pellets, than it is in men receiving intramuscular injections of shorter-acting androgen esters.

Ip and colleagues found that in men receiving long-acting depot testosterone treatment, the development of polycythemia (hematocrit >50%) was predicted by higher trough serum testosterone concentrations but not by the duration of treatment.[20]

Laboratory Studies

Testing for the JAK2 V617F mutation and an erythropoietin (EPO) level helps differentiate secondary polycythemia from polycythemia vera. Positive JAK2 V617F mutation status with a low EPO level confirms the diagnosis of polycythemia vera. If JAK2 V617F mutation testing is negative but the EPO level is low, then testing for other mutations in exon 12 and 13 of JAK2 helps identify a small minority of patients with polycythemia vera. All the other patients with wild-type JAK2 and a normal or elevated EPO level have secondary polycythemia.

Measure red blood cell mass and plasma volume when repeated hematocrit levels exceed 52% in males and 47% in females. However, data from the Polycythemia Vera Study Group showed that if the hematocrit value is 60% or higher, the red blood cell mass is always increased; formal red blood cell mass and plasma volume studies are unnecessary in those cases. As a practical note, most nuclear medicine departments perform these tests very infrequently, which may raise questions about the reliability and validity of red blood cell mass and plasma volume measurements.

To measure red blood cell mass, calculate the total red blood cell mass from the dilution factor and a known volume of radiolabeled (chromium-51 [51 Cr]) autologous red blood cells. The red blood cell mass is increased if it exceeds 35 mg/kg in males and 31 mg/kg in females. Documentation of an increased red blood cell mass is essential to demonstrate true erythrocytosis.

To measure plasma volume, use radiolabeled albumin (iodine-131 [131 I]), similar to the process used with the red blood cell mass measurement. Plasma volume can also be calculated indirectly using total red blood cell mass and the hematocrit value.

Decreased plasma volume with a normal red blood cell mass indicates a relative polycythemia or erythrocytosis, similar to the increased hemoglobin and hematocrit levels associated with severe dehydration. Decreased plasma volume due to dehydration is the most common cause of elevated hemoglobin or hematocrit levels in the general population.

Measuring arterial oxygen saturation is important to exclude generalized hypoxemia as a cause of increased red blood cell mass. Further investigation may require performing the test while the patient is sleeping. Measured arterial oxygen saturations of less than 92% may be associated with the development of a secondary polycythemia.

Carboxyhemoglobin levels of greater than 8% in individuals who smoke or those who may have an occupational exposure to carbon monoxide may be associated with the development of polycythemia.

The hemoglobin-oxygen dissociation curve may be determined in patients with a lifelong history (particularly a familial history) of erythrocytosis with normal oxygen saturation and normal levels of 2,3-diphosphoglycerate.

Formulas are available in which the measured arterial and venous oxygen saturations can be used to calculate the partial pressure of oxygen (PaO2) at which hemoglobin is 50% saturated with oxygen. This partial pressure value is a good estimate of the entire oxygen dissociation curve, because the shape of the dissociation curve varies only minimally, even with very high and very low oxygen affinity hemoglobins.

Endogenous serum levels of EPO may be helpful to determine inappropriate production of EPO. Serum EPO levels also may be very helpful in distinguishing between primary and secondary polycythemias.[7, 21]

In polycythemia vera and congenital/familial primary polycythemias, EPO levels are usually low to low-normal. In secondary physiologic or nonphysiologic polycythemias, EPO levels are usually normal or elevated.

Imaging Studies

An abdominal computed tomography (CT) scan or an intravenous pyelogram to investigate the kidneys and their function may be indicated in a minority of patients who may have a tumor or renal abnormalities that may be causing the polycythemia.

Histologic Findings

Increased total red blood cell mass determines true polycythemia. Secondary causes must be identified individually.

Medical Care

The development of secondary erythrocytosis in response to tissue hypoxia is physiologic and probably beneficial to many patients. The expanded red blood cell mass may partially or totally compensate for the lack of oxygen delivery and result in tissue oxygenation to its normal level.

At hematocrit levels higher than 60-65%, however, the compensatory increase in red blood cells reaches the limit of benefit and begins to compromise circulation because of hyperviscosity. The latter leads to greater tissue hypoxia and erythropoietin secretion, a continued increase in red blood cells, and further impairment of circulation.

To restore viscosity and maintain circulation at its optimal level, phlebotomize or remove the offending red blood cells. Some patients with extreme secondary polycythemia have impaired alertness, dizziness, headaches, and compromised exercise tolerance. They may also be at increased risk for thrombosis, strokes, myocardial infarction, and deep vein thrombosis. These are the patients who require phlebotomy.

The optimal level of hematocrit is one that is as close as possible to normal without impairing the compensatory benefit of increased oxygen delivery. This may be determined individually by symptom relief or decompensation, depending on the viscosity level.

Repeated phlebotomies result in iron deficiency that can cause other symptoms.[22] This may limit or retard further erythropoiesis so that additional phlebotomies may not be necessary. Proper treatment of the underlying condition in polycythemia, when possible, is important, such as the following:

Surgical Care

Some cases of secondary polycythemia are caused by conditions that can be ameliorated by surgical removal or correction.

Medication Summary

No medications are available to treat the blood disorder of secondary polycythemia. Treat the underlying health problem.

Complications

Prognosis

Author

Srikanth Nagalla, MBBS, MS, Director, Clinical Hematology, Cardeza Foundation for Hematologic Research; Assistant Professor of Medicine, Division of Hematology, Associate Program Director, Hematology/Medical Oncology Fellowship, Assistant Program Director, Internal Medicine Residency, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

Coauthor(s)

Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

Specialty Editors

Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Disclosure: Novartis Honoraria Speaking and teaching; Novartis Consulting fee Speaking and teaching; Ariad Honoraria Speaking and teaching; Celgene Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Ronald A Sacher, MB, BCh, MD, FRCPC, Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Disclosure: Alexion Honoraria Speaking and teaching

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Disclosure: Nothing to disclose.

Chief Editor

Koyamangalath Krishnan, MD, FRCP, FACP, Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine, James H Quillen College of Medicine at East Tennessee State University

Disclosure: Nothing to disclose.

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